Cirrhosis and chronic pancreatitis are well-established risk factors for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) respectively. The fibrotic stroma actively contributes to carcinogenesis, metastasis, and resistance to therapy. Formation of the fibrotic stroma occurs through activation of resident quiescent stellate cells to a myofibroblast state, which is characterized by excessive secretion of extracellular matrix (ECM) components and growth factors. Transforming growth factor-? (TGF-??) signaling plays a central role in promoting this pathological activation during cirrhosis, pancreatitis, and carcinogenesis. The type III TGF-? receptor (T?RIII) mediates TGF-? signaling through regulation of ligand binding and interaction with the cytoplasmic proteins ?-arrestin2, GIPC, and the E3 ubiquitin ligase TRAF6. T?RIII inhibits migration, invasion, and metastasis in multiple epithelial-derived cancers, with T?RIII expression frequently lost during cancer progression. TGF-? induces p38 MAPK signaling via TRAF6, and our preliminary studies indicate TGF?-p38 MAPK signaling plays an important role in promoting myofibroblast activation. However, the role of the T?RIII-TRAF6 interaction in TGF?-induced p38 MAPK signaling remains to be elucidated. Based on preliminary studies showing T?RIII expression is lost during myofibroblast activation, the following hypothesis is proposed: T?RIII homeostatically inhibits stellate cell activation through TRAF6-mediated inhibition of TGF?-induced p38 MAPK signaling, resulting in inhibition of cancer progression, with loss of T?RIII expression during stellate cell activation in the fibrotic stroma of PDAC and HCC contributing to cancer progression. This hypothesis will be addressed by 3 specific aims. Specific Aim 1: The role of T?RIII will be examined in in vitro stellate cell activation and in viv models of toxin-induced fibrosis to determine whether T?RIII regulates TGF?-induced myofibroblast activation and ECM secretion. Specific Aim 2: The contribution of the T?RIII-TRAF6 interaction to TGF?-induced p38 MAPK signaling and the effect of this pathway on stellate cell activation and cancer progression will be established. Specific Aim 3: The contribution of T?RIII expression in stellate cells to the biology of the neighboring cancer cells will be established to determine whether loss of T?RIII expression during stellate cell activation contributes to tumor growth and metastasis. These studies will determine the role of T?RIII in myofibroblast activation and ECM secretion, facilitating targeting of the fibrotic stroma for the treatment of these deadly cancers.